Cancer is a leading cause of death in the industrialized world and despite years of research, many types of cancer lack an effective therapeutic treatment. This is especially true for cancers that are characterized by the presence of large, solid tumors, since it is difficult to deliver an effective dose of a chemotherapeutic agent to the interior of a large tumor mass with a significant degree of selectivity. Moreover, due to the genetic instability of tumor cells, a tumor tissue can rapidly acquire resistance to standard therapeutic regimens.
In order to develop into a large solid tumor mass, however, tumor foci must first establish a network of blood vessels in order to obtain the nutrients and oxygen that are required for continued growth. The tumor vascular network has received enormous interest as a therapeutic target for antineoplastic therapy because of its accessibility to blood-borne chemotherapeutics and the relatively small number of blood vessels that are critical for the survival and continued growth of the much larger tumor mass. Disruption in the function of a single tumor blood vessel can result in an avalanche of ischaemic tumor cell death and necrosis of thousands of cancer cells that depend on it for blood supply. In addition, the accessibility of the tumor vasculature to blood-borne anticancer agents and the relatively stable genome of normal, host vascular tissue can alleviate some of the problems such as bioavailability and acquired drug resistance that are associated with conventional, anti-tumor based therapies.
Much of the research in anti-vascular cancer therapy has focused on understanding the process of new blood vessel formation, known as angiogenesis, and identifying anti-angiogenic agents that inhibit the formation of new blood vessels. Angiogenesis is characterized by the proliferation of tumor endothelial cells that form new vasculature to support the growth of a tumor. This growth is stimulated by certain growth factors produced by the tumor itself. One of these growth factors, Vascular Endothelial Growth Factor (“VEGF”), is relatively specific towards endothelial cells, by virtue of the restricted and up-regulated expression of its cognate receptor. Various anti-angiogenic strategies have been developed to inhibit this signaling process at one or more steps in the biochemical pathway in order to prevent the growth and establishment of the tumor vasculature. However, anti-angiogenic therapies act slowly and must be chronically administered over a period of months to years in order to produce a desired effect.
Vascular Targeting Agents (“VTAs”), also known as Vascular Damaging Agents, are a novel class of antineoplastic drugs that exert their effects on solid tumors by selectively occluding, damaging, or destroying the existing tumor vasculature. This disruption of the tumor vasculature occurs rapidly, within minutes to hours following VTA administration, and manifests as a selective reduction in the flow to at least a portion of a tumor region or loss in the number of functional tumor blood vessels in at least a portion of a tumor region, leading eventually to tumor cell death by induction of hypoxia and nutrient depletion. The selectivity of the agent is evidenced by the fact that there are few adverse effects on the function of blood vessels in normal tissues. Thus, the anti-vascular mechanism of VTA action is quite divorced from that of anti-angiogenic agents that do not disrupt existing tumor vasculature but in contrast inhibit molecular signals which induce the formation of tumor neovasculature.
Combretastatin A-4 Disodium Phosphate Prodrug (“CA4P”) is the lead drug of a group of VTAs currently in clinical trials as a VTA. This compound was initially isolated as Combretastatin A-4 (“CA-4”) from the stem wood of the African tree Combretum caffrum (Combretaceae). CA4P has the following structure:

As described in U.S. Pat. No. 4,996,237, the entire disclosure of which is incorporated herein in entirety, CA-4 was synthesized and found to have potent tubulin binding activity. Moreover, CA-4 was found to be a potent inhibitor of microtubule assembly in tumor endothelium. However, due to the insolubility of CA-4 in human plasma, CA4P was developed (U.S. Pat. No. 5,561,122, the entire disclosure of which is incorporated by reference). When administered to the bloodstream of a patient, the CA4P is cleaved to the active, tubulin-binding CA-4 by endogenous nonspecific phosphatases. It is thought that CA-4 selectively destabilizes the microtubule cytoskeleton of tumor endothelial cells, causing a profound alteration in the shape of the cell which ultimately leads to occlusion of the tumor blood vessel and shutdown of blood flow to the tumor (Galbraith et al, Anticancer Research, 2001, 21:93-102; Kanthou and Tozer, Blood, 2002, 99(6): 2060-2069).
While in vivo studies have confirmed that vascular damaging effects of VTAs on tumor tissue far exceed their effects on normal tissues (Chaplin, et al., Anticancer Research, 1999, 19(1A): 189-196), only in a few cases has a tumor regression or complete tumor response been observed when these agents are used alone as a single agent therapy or monotherapy. The lack of traditional tumor response has been attributed to the rapid recolonization of the necrotic tumor core by a viable rim of tumor cells at the periphery of the tumor capable of receiving oxygen and nutrients from the surrounding normal tissue to resist the effects of blood flow shutdown (Chaplin, et al., Anticancer Research, 1999, 19(1A):189-196). While this viable rim is resistant to VTA therapy, it remains highly susceptible to conventional radiation, chemotherapy and antibody-based therapeutics, and many studies have demonstrated effective tumor regression when VTAs are used in combination with one of these therapies (Li and Rojiani, Int. J. Radiat. Oncol. Biol. Phys., 1998, 42(4): 899-903; Grosios et al., Anticancer Research, 2000, 20(1A): 229-233; Pedley et al., Cancer Research, 2001, 61(12): 4716-4722; WO 02/056692).
Despite the effectiveness when used in combination with VTA therapy, conventional therapies must be administered in repeat daily doses following initial VTA administration in order to achieve prolonged tumor regression. Most conventional therapies are highly cytotoxic, and the patient must cope with prolonged side effects (emesis, hair loss, myelosuppression, etc.) due to chronic administration. VTA therapies lack many of these toxic effects. There is therefore an urgent need in the art for a VTA compound which can be used effectively as a single agent and has the capacity to destroy tumor cells in all regions of the tumor, including the periphery.